BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Protein phosphatase 1 regulatory inhibitor subunit 15A (PPP1R15A; PEG-3); eukaryotic translation initiation factor 2 (eIF2) subunit 1α (eIF-2α; EI

April 23, 2015 7:00 AM UTC

In vitro and mouse studies suggest a selective inhibitor of PPP1R15A - the regulatory subunit of eIF-2α - could help treat ALS, Charcot-Marie-Tooth disease and other diseases involving protein misfolding. Chemical synthesis and testing of guanabenz analogs in a cell-based assay of endoplasmic reticulum stress identified a lead compound that inhibited PPP1R15A and decreased levels of proteins related to the stress response compared with vehicle. In a mouse model of ALS, the inhibitor decreased motor defects and weight loss compared with vehicle. In a mouse model of Charcot-Marie-Tooth Type IB disease, the inhibitor decreased motor defects and demyelination. Next steps include identifying additional diseases that could be treated with the PPP1R15A inhibitor...